Kinetic Modeling of 3′-Deoxy-3′-18F-Fluorothymidine for Quantitative Cell Proliferation Imaging in Subcutaneous Tumor Models in Mice

Authors:
  • JLJae Sung Lee
    Jae Sung Lee
  • KIKi Chum Im
    Ki Chum Im
  • SKSeog-Young Kim
    Seog-Young Kim
  • SPSoo-Ah Park
    Soo-Ah Park
  • SLSeung Jin Lee
    Seung Jin Lee
  • SOSeung Jun Oh
    Seung Jun Oh
  • DLDong Soo Lee
    Dong Soo Lee
  • DMDae Hyuk Moon
    Dae Hyuk Moon
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Abstract
3′-Deoxy-3′-18F-fluorothymidine (18F-FLT) is a thymidine analog that was developed for measuring tumor proliferation with PET. The aim of this study was to establish a kinetic modeling analysis method for quantitative 18F-FLT PET studies in subcutaneous tumor models in mice. Methods: To explore the validity of an image-derived left ventricular input function, we measured equilibrium constants for plasma and whole blood and metabolite fractions in blood after 18F-FLT injection. In parallel, dynamic 18F-FLT PET scans were acquired in 24 mice with a small-animal dedicated PET scanner to compare arterial blood activities obtained by PET and blood sampling. We then investigated kinetic models for 18F-FLT in human epithelial carcinoma (A431) and Lewis lung carcinoma tumor models in mice. Three-compartment models with reversible phosphorylation (k4 ≠ 0, 3C5P) and irreversible phosphorylation (k4 = 0, 3C4P) and a 2-compartment model (2C3P) were examined. The Akaike information criterion and F statistics were used to select the best model for the dataset. Gjedde–Patlak graphic analysis was performed, and standardized uptake values in the last frame were calculated for comparison purposes. In addition, quantitative PET parameters were compared with Ki-67 immunostaining results. Results: 18F-FLT equilibrated rapidly (within 30 s) between plasma and whole blood, and metabolite fractions were negligible during PET scans. A high correlation between arterial blood sampling and PET data was observed. For 120-min dynamic PET data, the 3C5P model best described tissue time–activity curves for tumor regions. The net influx of 18F-FLT (KFLT) and k3 obtained with this model showed reasonable intersubject variability and discrimination ability for tumor models with different proliferation properties. The KFLT obtained from the 60- or 90-min data correlated well with that obtained from the 120-min data as well as with the Ki-67 results. Conclusion: The image-derived arterial input function was found to be feasible for kinetic modeling studies of 18F-FLT PET in mice, and kinetic modeling analysis with an adequate compartment model provided reliable kinetic parameters for measuring tumor proliferation.

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